Acrylic adhesive for assembling elements contacting biological substances

ABSTRACT

The present invention relates to acrylic adhesive composition comprising a mixture of at least one polyol tri(meth)acrylate monomer and at least one polyalkylene glycol mono(meth)acrylate monomer for assembling elements made of plastic materials, like PMMA or SAN, or inorganic material, like glass or metals, employed for manufacturing of devices for the distribution or containment of biological substances, like proteins, enzymes, antibodies, antigens, DNA, and the like. The present invention also relates to devices for the distribution or containment of biological substances assembled with the above mentioned acrylic adhesive composition, and particularly thermal or piezoelectric ejecting devices, and biochip microarray, as well as to a method for assembling thereof.

FIELD OF THE INVENTION

The present invention relates to an acrylic adhesive for assemblingelements contacting biological substances and to a device assembledtherewith.

More in particular, the present invention relates to acrylic adhesivecomposition comprising a mixture of at least one polyoltri(meth)acrylate monomer and at least one polyalkylene glycolmono(meth)acrylate monomer for assembling elements made of plasticmaterials, like PMMA or SAN, or inorganic material, like glass ormetals, employed for manufacturing of devices for the distribution orcontainment of biological substances, like proteins, enzymes,antibodies, antigens, DNA, and the like.

The present invention also relates to devices for the distribution orcontainment of biological substances assembled with an acrylic adhesivecomposition, and particularly thermal or piezoelectric ejecting devices,and biochip microarray.

BACKGROUND OF THE INVENTION

In the biomedical field devices are known for the distribution orcontainment of biological substances, like proteins, enzymes,antibodies, antigens, DNA, and the like, dissolved in solutions orbiological fluids.

Such biomedical devices are manufactured by assembling differentcomponents of different materials by adhesive compositions. Severalpatents and patent publications describe such kind of devices.

U.S. Pat. No. 5,338,688 describes a device for ejecting biologicalfluids comprising a reservoir connected with an ejection chamberprovided with a heating element. U.S. Pat. No. 4,877,745 describes asimilar device, wherein the ejection chamber is provided with apiezoelectric element.

U.S. Pat. No. 6,830,621 describes a liquid discharge apparatuscomprising (i) a liquid holding portion for holding the probe liquid,(ii) a supply opening for supplying the probe liquid to the liquidholding portion, (iii) a liquid discharging nozzle for discharging theprobe liquid, and (iv) a flow path connecting the nozzle with the liquidholding portion. The nozzle openings and the supply opening are disposedon mutually opposed faces of the apparatus. The apparatus has alaminated structure composed of a first plate-shaped member in whichsaid nozzles are formed, and a second plate-shaped member in which saidplurality of liquid supply opening are formed, and intermediateplate-shaped members in which the flow path connecting the nozzle withthe liquid holding portion is realized.

EP 1,933,138 discloses microarrays of capture probes on a substrate tobe used in biological assays, for instance to examine analyte biologicalfluids, such as human blood or tissue samples, for the presence and/orconcentration of certain bacteria, viruses and/or fungi. The captureprobes have a selective binding capacity for a predetermined indicativefactor, such as a protein, DNA or RNA sequence. In the microarraytechnique, a set of specific capture probes, each of which being chosenin order to interact specifically (e.g. hybridize in the case of a DNAmicroarray) with one particular target biological compound, areimmobilized at specific locations of a biosensor solid substrate, forinstance by printing. Suitable probes may comprise bio-fluids containingthe specific indicative factor, for instance a solution of a specificDNA sequence and/or antibody. After the substrate has been provided withthe capture probes, for instance by printing them on the substrate usingan ink jet device, the analyte fluid is forced to flow through thesubstrate, or is forced to flow over the substrate. In order to be ableto visualize the presence of an indicative factor in the analyte fluid,molecules of the analyte fluid may for instance be provided withfluorescent and/or magnetic labeling. In case of an ELISA (enzyme-linkedimmunosorbent assay) an enzyme is attached to the second antibody,instead of a radiolabel. An intensely colored or fluorescent compound isthen formed by the catalytic action of this enzyme. The labeledmolecules of the analyte fluid adhere to those capture probes of thesubstrate that have binding capacity for the molecule considered. Thisresults in a detectable fluorescence on the spot the specific factoradheres to, at least when using fluorescent labeling. The capturedmolecules are typically read by illumination with a light source, andthe fluorescent pattern recorded with the aid of a CCD camera forinstance. The recorded pattern is a characteristic of the presence of abacterium or a set of bacteria. By providing capture probes withdifferent specificity for different factors, the array may be used toassay for various different factors at the same time. Using such arraysenables high-throughput screening of analyte fluids for a large amountof factors in a single run.

The main problem of the biomedical devices obtained by assemblingdifferent components of different materials by adhesive compositionsrelates to the reduction of the adhesion strength under aging, inparticular when different materials (like metals, silicon, plastics, orglass) are contacting each other and are exposed to mechanical andthermal stresses.

Moreover, the components of the biomedical devices described in the art,in particular in the microelectronic and microhydraulic fields employedin the technology derived from ink-jet printing, must be biocompatiblewith the biological substances. Accordingly, the component materialsshould not hold the biological substances on their surface and shouldnot release any contaminant substance into the biological fluid.

Additionally, the component material surface should have a highwettability to allow an easy diffusion of the biological fluids,typically having an aqueous base, into the biomedical device. Thewettability is even more important in devices containing microhydraulicconduits wherein the flow of the fluids depends on capillarity forcesand interactions between the fluid and the contacting surface.

Surface treatments are known in the art to reduce the chemical andphysical interactions between the material surfaces and the biologicalfluids, such as, for example, plasma treatment, corona treatment, orfilm coating. However, plasma and corona treatments have a limitedduration over time. Film coating treatments which alter the materialsurface, can also make difficult the subsequent adhesion of thecomponents and its strength under aging.

SUMMARY OF THE INVENTION

The Applicant has surprisingly found that the above mentioned problemscan be overcome by assembling the components of a biomedical device forthe distribution or containment of biological substances with anadhesive composition comprising a mixture of at least one polyoltri(meth)acrylate monomer and at least one polyalkylene glycolmono(meth)acrylate monomer.

A first aspect of the present invention relates to a biomedical devicefor the distribution or containment of biological substances comprisingat least two components assembled each other with an adhesivecomposition comprising at least one polyol tri(meth)acrylate monomer andat least one polyalkylene glycol mono(meth)acrylate monomer.

In another aspect the present invention relates to a biomedical devicefor the distribution or containment of biological substances comprisingat least one surface thereof covered with a cured acrylic compositionlayer having a wettability equal to or lower than 50°.

Another aspect of the present invention relates to a method forassembling a biomedical device comprising at least two components,wherein said process comprises the steps of (i) forming a film of anadhesive composition comprising at least one polyol tri(meth)acrylatemonomer and at least one polyalkylene glycol mono(meth)acrylate monomeron at least one surface of said at least two components, (ii) contactingsaid at least one surface of said at least two components to beassembled, and (iii) curing said adhesive composition.

A further aspect of the present invention relates to an adhesivecomposition comprising at least one polyol tri(meth)acrylate monomer, atleast one polyalkylene glycol mono(meth)acrylate monomer, and at leastone radical initiator.

A still further aspect of the present invention relates to the use ofthe above mentioned adhesive composition for assembling the componentsof a biomedical device for the distribution or containment of biologicalsubstances.

The adhesive composition of the present invention comprises a mixture ofat least one polyol tri(meth)acrylate monomer, at least one polyalkyleneglycol mono(meth)acrylate monomer, and at least one radical initiator.

The polymerizable polyol tri(meth)acrylate monomers, used pursuant tothe invention, are preferably selected from triacrylates, such asditrimethylolpropane triacrylate (DiTMPTTA),tris-(2-hydroxyethyl)-isocyanurate triacrylate (THEICTA),dipentaerythritol triacrylate (DiPETA), ethoxylated trimethylolpropanetriacrylate (TMPEOTA), propoxylated trimethylolpropane triacrylate(TMPPOTA), ethoxylated pentaerythritol triacrylate (PETEOIA),propoxylated glyceryl triacrylate (GPTA), pentaerythritol triacrylate(PETA), trimethylolpropane triacrylate (TMPTA) and modifiedpentaerythritol triacrylate; and trimethacrylates, such astriethyleneglycol trimethacrylate (TIEGTMA), tetraethyleneglycoltrimethacrylate (TTEGTMA), polyethyleneglycol trimethacrylate (PEGTMA),trihydroxyhexane trimethacrylate (HTTMA), ethoxylated bisphenol Atrimethacrylate, trimethylolpropane trimethacrylate (TMPTMA).

Preferably, ethoxylated or propoxylated polyol tri(meth)acrylatemonomers are utilized in the adhesive composition. The use ofethoxylated or propoxylated polyol tri(meth)acrylate monomers improvesthe wettability of the resulting surfaces covered with the adhesivecomposition. The wettability of a cured adhesive composition layer, whenmeasured with the contact angle method by using a drop of watercontacting the adhesive composition layer, is equal to or lower than50°, preferably lower than 40°, and more preferably lower than 35°.Also, the use of ethoxylated or propoxylated polyol tri(meth)acrylatemonomers, typically having a low viscosity, allows to reduce theviscosity of the adhesive composition.

Examples of preferred ethoxylated or propoxylated polyoltri(meth)acrylate monomers include, but are not limited to, ethoxylatedtrimethylolpropane triacrylate (TMPEOTA), propoxylatedtrimethylolpropane triacrylate (TMPPOTA), ethoxylated pentaerythritoltriacrylate (PETEOIA), propoxylated glyceryl triacrylate (GPTA),ethoxylated bisphenol A trimethacrylate, ethoxylated trimethylolpropanetrimethacrylate (TMPETMA), commercially available, for example, from IGMResins, under the tradename Omnimer®.

The acrylic adhesive composition of the present invention preferablycomprises from about 40% to about 90% by weight, based upon the totalweight of the composition, of the polyol tri(meth)acrylate monomers.According to a preferred embodiment, the adhesive composition of thepresent invention preferably comprises from about 50% to about 80% byweight, based upon the total weight of the composition, of the polyoltri(meth)acrylate monomers.

The polymerizable polyalkylene glycol mono(meth)acrylate monomers, usedpursuant to the invention, are preferably selected from (meth)acrylatessuch as polypropylene glycol monomethacrylate, polyethylene glycolmonomethacrylate, polyethylene glycol-polypropylene glycolmonomethacrylate, polypropylene glycol monoacrylate, polyethylene glycolmonoacrylate, polypropylene glycol-polytrimethylene monoacrylate,polyethylene glycol-polytetramethylene glycol monomethacrylate,methoxypolyethylene glycol monomethacrylate,perfluoroalkylethyl-polyoxyalkylene monomethacrylate, and combinationsthereof. Commercial products of those compounds are available,including, for example, Blemmer PP series (polypropylene glycolmonomethacrylates), Blemmer PE series (polyethylene glycolmonomethacrylates), Blemmer PEP series (polyethyleneglycol-polypropylene glycol monomethacrylate), Blemmer AP-400(polypropylene glycol monoacrylate), and Blemmer AE-350 (polyethyleneglycol monoacrylate). These are all products of Nippon Oils & Fats Co.

The acrylic adhesive composition of the present invention preferablycomprises from about 5% to about 35% by weight, based upon the totalweight of the composition, of the polyalkylene glycol mono(meth)acrylatemonomers. According to a preferred embodiment, the adhesive compositionof the present invention preferably comprises from about 10% to about30% by weight, based upon the total weight of the composition, of thepolyalkylene glycol mono(meth)acrylate monomers.

The Applicant has found that when the polyalkylene glycolmono(meth)acrylate monomers is added to the acrylic adhesive compositionin an amount within the above mentioned range, the cured compositionexhibits excellent antifouling and adhesion properties.

Moreover, the surface of the materials treated with the adhesivecomposition of the present invention which remain exposed, i.e., notjoined to the surface of another material, resulted to be biocompatiblewith the biological fluids. In other words, the surface of the materialstreated with the adhesive composition of the present invention neitherlinks external components contained in the biological fluids contactingit, nor releases internal components which could alter the compositionof the biological fluids contacting it.

Accordingly, the use of the acrylic adhesive composition of the presentinvention allows to avoid all those surface treatments, like thermaltreatment, corona treatment, plasma treatment, and so on, whichconventionally are employed to improve the biocompatibility andantifouling properties.

Without being limited by any theory, the Applicant believes that thebiocompatibility and the antifouling properties are due to the presenceon the surface of the cured composition of polyalkylene glycol chainswhich prevent or reduce the absorption of biomolecules like proteins,enzymes, DNA, and so on.

The free-radical polymerization of the acrylic adhesive composition ofthe present invention can be carried out in any manner familiar to theskilled worker, for example thermally, photochemically, and/or by meansof electron beams. Preferably, the free-radical polymerization iscarried out photochemically.

Accordingly, the acrylic adhesive composition of the present inventioncomprises from about 1% to about 25%, more preferably from about 2% toabout 20% by weight based upon the total weight of the composition, of athermal initiator (thermoinitiator) or an initiator sensitive to UVand/or blue radiation (photoinitiator). As used herein, “photoinitiator”means a suitable compound which is capable of converting the UV and/orblue radiation energy into free radicals. As used herein,“thermoinitiator” means a suitable compound which is capable ofconverting the thermal energy into free radicals. The presence of thefree radicals initiates a chain reaction which converts reactive monomercompounds into oligomers and ultimately into polymers.

Examples of suitable photoinitiators include but are not limited to:2,2′-(2,5-thiophenediyl)bis(5-tert-butylbenzoxazole);1-hydroxycyclohexyl phenyl ketone; 2,2-dimethoxy-2-phenylacetophenone;xanthone; fluorenone; anthraquinone; 3-methylacetophenone;4-chlorobenzophenone; 4,4′-dimethoxybenzophenone;4,4′-diaminobenzophenone; Michler's ketone; benzophenone; benzoin propylether; benzoin ethyl ether; benzyl dimethyl ketal,1-(4-isopropylphenyl)-2hydroxy-2-methylpropane-1-one;2-hydroxy-2-methyl-1phenylpropane-1 one; methylbenzoyl formatethioxanthone; diethylthioxanthone; 2-isopropylthioxanthone;2-chlorothioxanthone;2-methyl-1-(4-(methylthio)phenyl)-2-morpholinopropane-1-one; and2,4,6-trimethylbenzoyldiphenylphosphine oxide.

Preferably, multifunctional photoinitiators are utilized in the adhesivecomposition. The use of multifunctional photoinitiators further reducesthe possibility of photoinitiator or fragments of the photoinitiatorfrom migrating. Examples of suitable multifunctional photoinitiatorsinclude, but are not limited to, the Esacure KIP 100 (a mixture of 70%of an oligomeric α-hydroxy acetophenone and 30% of dimethyl hydroxyacetophenone), KIP 150, Esacure KTO-46 (blend of trimethylbenzophenone,polymeric hydroxy ketone, and trimethylbenzoyldiphenyl phosphine oxide),and Esacure ONE (difunctional alpha-hydroxyketone photoinitiator), allcommercially available from Lamberti S.p.A., Gallarate, Italy).

The Applicant has found that when the adhesive composition of thepresent invention comprises the above mentioned multifunctionalphotoinitiators, it can be cured even employing a curing radiationhaving a low energy, i.e., having a wavelength ranging from 400 to 450nm (violet light) and even ranging from 450 to 500 nm (blue light). Thisis particularly advantageous when curing components (like covers) ofbiological devices already filled with biological fluids that could bealtered, or even destroyed, by exposure to radiation of high energy(like UV radiation having wavelength lower than 400 nm).

Suitable thermal initiators include organic peroxides in the form ofdiacyl peroxides, peroxydicarbonates, alkyl peresters, dialkylperoxides, perketals, ketone peroxides and alkyl hydroperoxides, andalso azo compounds. Concrete examples of such thermal initiators aredibenzoyl peroxide, tert-butyl perbenzoate, tert-butylperoxide,methylethylketone peroxide, and azobisisobutyronitrile.

The acrylic adhesive composition of the present invention preferablycomprises from about 0.01% to about 2% by weight of a flow agent, basedupon the total weight of the composition. In a preferred embodiment, thecomposition includes from about 0.02% to about 1% by weight of a flowagent. As used herein, “flow agent” means a suitable surface wetting orleveling agent. Preferably, the flow agent is a siloxane. Morepreferably, the siloxane is polyester modified dimethyl polysiloxane. Asuitable commercially available product is Byk 310® (Byk Chemie;Wallingford, Conn.). Most preferably, the composition includes about0.1% of Byk 310®.

The acrylic adhesive composition of the present invention preferablycomprises from about 1% to about 20%, preferably from about 2% to about15% by weight, based upon the total weight of the composition, of atleast one coupling agent. The coupling agent can especially be acompound chosen from the silane compounds, such as, for example,aminosilanes, and unsaturated silanes such as a vinylsilane or amethacrylsilane.

Examples of suitable silane compounds include, but are not limited to,the commercially available vinyltri(β-methoxyethoxy)silane (A172) orγ-methacryloxypropyltrimethoxysilane (A174), both marketed by UnionCarbide.

The Applicant has found that the addition of the above mentioned silanecompounds can improve the adhesion between glass and other surfaces,like silicon and plastic materials, like polymethylmethacrylate (PMMA)and styrene acrylonitrile (SAN).

The acrylic adhesive composition of the present invention preferablycomprises from about 1% to about 20%, preferably from about 5% to about10% by weight, based upon the total weight of the composition, of atleast one oxygen scavenger.

The oxygen scavenger can especially be a compound chosen fromsubstituted phenols, such as, for example, butylated hydroxy toluene(BHT) and mono-t-butyl hydroquinone (MTBHQ) and aromatic amines, suchas, for example, alkylated diphenyl amines and naphthylamines. BHT iscommercially available from the Uniroyal Chemical Company, while MTBHQis commercially available from the Eastman Chemical Company. Alkylateddiphenyl amines are commercially available from Monsanto, under theFlectol tradename series. Naphthylamines are commercially available fromMobay, under the Vukanox tradename series.

When the adhesive composition of the present invention comprises anoxygen scavenger, the curing step can be also performed in the presenceof oxygen. This is particularly advantageous when the biomedical devicecomprises areas or zones, like chambers isolated form a valve system,difficultly reached by a nitrogen flow.

The adhesive composition of the present invention can be advantageouslyemployed for assembling the components of a biomedical device for thedistribution or containment of biological substances. As describedabove, the components of the biomedical device to be joined can be madeof different materials, such as inorganic materials, like, for example,silicon, glass, aluminum and other metals conventionally employed, orplastic materials, like, for example, polymethylmethacrylate (PMMA),cyclic olefin copolymers (COC), polycarbonates (PC), styreneacrylonitrile copolymers (SAN), and the like. The adhesive compositionof the present invention has been proven to be able to join thecomponents made of the same or different material.

Biomedical devices for the distribution or containment of biologicalsubstances are known in the art.

As indicated above, a feature of a biomedical device for thedistribution of biological substances is the provision of a thermal orpiezoelectric ejection head to deposit a quantity of the biologicalfluid onto a substrate surface. Thermal and piezoelectric ejection headsare well known in the art of conventional printing and documentproduction.

As is known to those of skill in the art, thermal and piezoelectricejection heads typically have at least the following components: (a) anorifice; (b) an ejection chamber; and (c) an actuating element, whichcan be a heating or piezoelectric element. Ejection heads are typicallyformed on a silicon substrate comprising the electronic components tooperate the actuating element.

The size of the orifice is sufficient to produce a spot of suitabledimensions on the substrate surface, where the orifice generally has adiameter ranging from about 1 to 1000 μm, usually from about 5 to 100 μmand more usually from about 10 to 60 μm.

The ejection chamber has a volume ranging from about 1 pl to 10 nl,usually from about 10 pl to 5 nl and more usually from about 35 pl to1.5 nl.

The actuating element is realized to deliver a quick energy pulse,either in the thermal or pressure form. The heating element is capableof achieving temperatures sufficient to vaporize a sufficient volume ofthe biological fluid in the ejection chamber to produce a drop of apredetermined volume of biological fluid from the orifice. Generally,the heating element is capable of attaining temperatures of at leastabout 100° C., usually at least about 400° C., and more usually at leastabout 700° C., where the temperature achievable by the heating elementmay be as high as 1000° C. or higher. The piezoelectric element iscapable to change its dimension and to reduce the volume of the ejectionchamber under the action of an electrical pulse to produce a pressureable to eject a drop of a predetermined volume of biological fluid fromthe orifice.

A barrier layer defining the microhydraulic of the biomedical device isusually laminated on the silicon substrate. Alternatively, the barrierlayer may also be preformed and then assembled on the silicon substrate.The barrier layer is usually made with a photopolymer compound anddefine the supply chamber(s) and the microchannels supplying thebiological fluid to the ejection chamber. Representative photopolymercompounds suitable for fabricating the barrier layer include but are notlimited to: (1) epoxy polymers; (2) acrylic and melamine copolymers, (3)epoxy-acrylate copolymers, and (4) polyimides, although materialsgenerally classified as photoresists or solder-masks can be used forthis purpose. The barrier layer will have a thickness of from about 5 toabout 50 μm, preferably from 10 to 40 μm although this value may bevaried as needed. The microchannels have a diameter ranging from 100 to300 μm, preferably from 150 to 250 μm.

At least one additional layer is then assembled on the barrier layer.The additional layer(s) define(s) supply channels having a sizeprogressively increasing from the lowermost layer to the uppermostlayer. The last additional layer is provided with supply openings forsupplying the biological fluid connected to reservoir chambers forcontaining the biological fluid. In turn, the reservoir chambers areconnected to the supply chamber(s) of the barrier layer through theabove mentioned supply channels. The diameter of the supply channelsstarts from a 300 μm up to 1000 μm, and the diameter or diagonal(depending of its shape) of the reservoir chambers can be up to 2 mm.The additional layer(s) may be made of plastic material, such as, forexample, polymethylmethacrylate (PMMA) or styrene acrylonitrile (SAN),glass, or a combination thereof.

Finally, a cover layer can be optionally assembled on the uppermostlayer to seal the biomedical device after the biological fluid has beensupplied to substantially fill the above mentioned reservoir chambers,supply channels and supply chambers.

In turn, a feature of a biomedical device for the containment ofbiological substances is the provision of a discrete microarray ofcapture probes immobilized at specific locations of a solid substrate tobe used in biological assays, for instance to examine analyte biologicalfluids, such as human blood or tissue samples, for the presence and/orconcentration of certain bacteria, viruses and/or fungi. Such biomedicaldevice are commonly known as microarray biochip, or simply biochip. Inparticular, a biomedical device for the containment of biologicalsubstances can be constituted by (i) a transparent solid substrate onwhich a discrete microarray of capture probes has been deposited (ii) acontaining chamber realized by photolithographic technique in apolymeric layer to confine biological samples (serum, blood, cells,oligomers and so on) and reagents in correspondence with such amicroarray, (iii) a cover with input and output channels through whichthe biological samples are introduced and washed away.

The assembling of the several components of the above describedbiomedical devices is advantageously made by (i) forming a film of theadhesive composition of the present invention on at least one surface ofthe components to be joined, (ii) contacting the at least one surface ofthe components to be assembled, and (iii) curing the adhesivecomposition.

The film forming step (i) can be advantageously performed by spraycoating techniques. The spraying coating apparatus typically requires toemploy liquid having a viscosity lower than 100 cPoise. Liquids having aviscosity higher than 100 cPoise can also be used, but they requirededicated and expensive spraying coating apparatus, such as, forexample, EFD (Engineered Fluid Dispensing) apparatus. The adhesivecomposition of the present invention advantageously has a viscositylower than 100 cPoise, preferably lower than 80 cPoise. Accordingly, theadhesive composition of the present invention has a viscosity compatiblewith the requirements of spraying coating apparatus. This allows toavoid the use of organic solvents, which could potentially damage theplastic materials, and then allows to realize biomedical device withplastic materials.

Accordingly, the above mentioned film forming step (i) is advantageouslyperformed in the substantial absence of any solvent, i.e., it issolvent-free. The use of the adhesive composition of the presentinvention allows to obtain a coated film having a constant andhomogeneous thickness. The thickness of the coated film of adhesivecomposition is not particularly limited, and depends on the kind ofapparatus employed to coat it and to the desired application. Thethickness can range from about 1 μm (the lower limit being oftendependent from the spraying apparatus specifications) to about 500 μm,and even more. However, the thickness of the coated film of adhesivecomposition preferably ranges from about 5 μm to about 100 μm.

The Applicant has found that the surface of the materials treated withthe adhesive composition of the present invention which remain exposed,i.e., not joined to the surface of another material shows severalimproved characteristics.

First, the material surface has improved wettability, so allowing aneasy diffusion of the biological fluids, typically having an aqueousbase, into the biomedical device. The wettability is even more importantin devices containing microhydraulic conduits wherein the flow of thefluids depends on capillarity forces and interactions between the fluidand the contacting surface. The wettability of the material surfacecovered with the adhesive composition of the present invention, whenmeasured with the contact angle method by using a drop of watercontacting the adhesive composition layer, is equal to or lower than50°, preferably lower than 40°, and more preferably lower than 35°.

Second, the material surface has improved biocompatibility and exhibitsexcellent antifouling and protective properties. In other words, thesurface of the materials treated with the adhesive composition of thepresent invention neither links external components contained in thebiological fluids contacting it, nor releases internal components whichcould alter the composition of the biological fluids contacting it.

Preferably, the surface of the components to be joined is previouslysubjected to a plasma treatment. Plasma treatment is a widely knownprocessing technology that aims at modifying the chemical and physicalproperties of a surface by using a plasma-based material. Plasmatreatment includes plasma activation, plasma modification, plasmafunctionalization and plasma polymerization. Plasma processing is widelyused in the field of electronics, automotive, textile, medical andaeronautic. A general review about plasma technology can be found on theEuroplasma internet site at http://www.europlasma.be/pageview.aspx.

The plasma treatment is performed by flowing a plasma gas on the surfaceof the components in an apparatus comprising a plasma chamber poweredwith a couple of electrodes. Any conventional plasma gas can be used,provided that it is free from oxygen, either in atomic and molecularform. The Applicant has observed that the presence of oxygen reduces theadhesion strength because the oxygen adsorbed on the surface inhibitsthe curing of the adhesive composition. The plasma gas is preferablyselected from the group consisting of saturated and unsaturatedhydrocarbons, nitrogen-containing hydrocarbons, nitrogen, ammonia,hydrogen, and mixture thereof. Saturated hydrocarbons, such as, forexample, methane and ethane, and forming gas, a mixture of nitrogen andhydrogen with a 10%, preferably 5%, maximum content of hydrogen, arepreferably used in the process of the present invention. Morepreferably, the forming gas useful in the process of the presentinvention comprises a mixture of 95% of nitrogen and 5% of hydrogen.Preferably, the mixture of methane and forming gas has a methane toforming gas weight ratio of from 1:5 to 5:1, more preferably from 1:3 to3:1 and most preferably from 1:2 to 2:1.

The plasma apparatus typically includes a chamber containing positiveand ground electrodes attached to a radio frequency (RF) generator. Thechamber comprises a support which is positioned between the positive andground electrodes. The support is properly isolated from the chamberwalls. The components to be treated are preferably put on the supportbetween the positive and ground electrodes. Alternatively, thecomponents can also be put in contact with the positive electrode or theground electrode. In operation, a vacuum is created within the chamberuntil a pre-selected pressure in the range of from 1 to 30 milliTorr,preferably from 5 to 20 milliTorr is reached.

The gas is usually introduced into the chamber for a time of from 15seconds to 3 minutes until to achieve the desired flow rate and partialpressures. The flow rate is preferably comprised from 1 to 300 sccm,more preferably form 10 to 200 sccm, and most preferably from 50 to 150sccm (sccm=Standard Cubic Centimeters per Minute). The partial pressuresis preferably comprised from 10 to 500 milliTorr, more preferably from30 to 300 milliTorr, and most preferably from 50 to 250 milliTorr. Oncethe flow rate and pressure in the chamber are stabilized, a high voltageis applied in the radio frequency range of the apparatus between theground and the positive electrodes and is maintained for the requiredtime. The radio frequency power is preferably in the range of from 10 to1000 Watt, more preferably from 30 to 700 Watt, and most preferably from50 to 400 Watt. Preferably, the plasma treatment is conducted for aperiod of time in the range of from 10 seconds to 60 minutes, morepreferably from 20 seconds to 30 minutes, and most preferably from 30seconds to 10 minutes.

The plasma treatment can be conducted under constant conditions, i.e.,without modifying the above described values of gas flow rate, gasmixture, pressure, and power, or under variable conditions.

Advantageously, the contacting step (ii) is performed by using apparatusprovided with centering means able to line up the components to bejoined. Preferably, the contacting step (ii) is followed by the removalof the air possibly trapped between two surfaces. The air removal ispreferably performed by subjecting the contacted surface to a reducedpressure, such as, for example, 50 mmHg or even less. Further, theexcess of adhesive can also been removed from channels and/or recessesof the components by subjecting the components to the action of vacuumapparatus.

Advantageously, when using adhesive compositions comprising a couplingagent like a silane compound, a thermal treatment of from 1 to 30minutes, preferably from 2 to 15 minutes, at a temperature of from 50 to200° C., preferably from 80° to 150° C., is made after the formation ofthe film of adhesive composition.

Generally, the curing step (iii) can be performed by exposure toradiation having a wavelength in the UV-blue range, namely from 200 to500 nanometers. The energy of the UV-blue radiation is absorbed by aphotoinitiator, which is capable of converting the light energy intofree radicals. The presence of the free radicals initiates a chainreaction which converts reactive monomer compounds into oligomers andultimately into polymers. Advantageously, when the curing step isperformed in the presence of biological compounds easily damaged by highenergy UV-radiation, the curing step is performed by exposure toradiation having a wavelength in the violet-blue range, namely from 400to 500 nanometers.

Usually, the curing step is performed under an oxygen-free atmosphere,typically under a nitrogen atmosphere, to avoid the above mentionedinhibiting effect that oxygen has on the radical polymerization. Anyway,when the adhesive composition of the present invention comprises anoxygen scavenger, like for example, tertiary aromatic amines, the curingstep can be also performed in the presence of oxygen. This isparticularly advantageous when the biomedical device comprises areas orzones, like chambers isolated form a valve system, difficulty reached bya nitrogen flow.

The curing step (iii) can also be performed by thermal treatment. Inthis case a thermal initiator (thermoinitiator) is preferably added tothe polymerization mixture. The polymerization temperature dependsprimarily on the decomposition temperature of the thermal initiator, butis preferably not higher than 135° C., and in particular, not higherthan 110° C. A combination of photochemical curing with thermal curingcan also be employed. In this case, thermal curing is preferablyperformed after photochemical curing.

The amount of biological fluid required to fill the biomedical device istypically small, generally not exceeding more than about 10 usually notexceeding more than about 5 μl and in many embodiments not exceedingmore than about 2 μl. As such, the amount of biological fluid that iswasted during filling is minimal. As such, fluid loading is highlyefficient. Therefore, the biomedical device of the present invention isparticularly suited for use with rare and/or expensive biological fluidsamples.

Biological fluid samples include solution or suspension of biologicalmolecular compounds such as, but not limited to, nucleic acids andrelated compounds (e.g. DNAs, RNAs, oligonucleotides or analogs thereof,PCR products, genomic DNA, bacterial artificial chromosomes, plasmidsand the like), proteins and related compounds (e.g. polypeptides,monoclonal antibodies, receptors, transcription factors, and the like),antigens, ligands, haptens, carbohydrates and related compounds (e.g.polysaccharides, oligosaccharides and the like), cellular organelles,intact cells, biopolymers and the like.

The filled and optionally sealed biomedical distribution device can beused to deposit an extremely small quantity of the biological fluid on aproper support, where the support may be a planar structure, e.g., aslide, a reagent container, e.g., a well in a multiwell plate (such asthe bottom of a well), a channel or micro structure, an array, and soon.

The biomedical distribution device of the present invention can be usedto deposit a pico liter quantity of fluid onto an array surface. By“pico liter quantity” is meant a volume of fluid that is at least about0.1 pl, usually at least about 1 pl and more usually at least about 10pl, where the volume may be as high as 250 pl or higher, but generallydoes not exceed about 100 nL and usually does not exceed about 1 μl.

In turn, biomedical containment device of the present invention can beused with extremely small quantity of the biological sample fluid (likeblood, urine, intestinal fluids or saliva), with improved cleaning andsterile conditions, and ease of use. Typically, the biomedicalcontainment device of the present invention can contain from 10 μl to500 μl of biological sample fluid depending on the volume of thecontaining chamber, which in turn depends on the chamber shape andthickness.

The use of the adhesive composition of the present invention presentedseveral advantages.

As mentioned above, the cured composition exhibits excellent antifoulingand adhesion properties.

Additionally, the surface of the materials treated with the adhesivecomposition of the present invention which remains exposed, such as, forexample, the surface of supply chamber(s), microchannels, supplychannels, and reservoir chambers, resulted to be biocompatible with thebiological fluids. In other words, the surface of the materials treatedwith the adhesive composition of the present invention neither linksexternal components contained in the biological fluids contacting it,nor releases internal components which could alter the composition ofthe biological fluids contacting it.

Accordingly, the use of the acrylic adhesive composition of the presentinvention allows to avoid or limit all those surface treatments, likethermal treatment, corona treatment, plasma treatment, and so on, whichconventionally are employed to improve the biocompatibility andantifouling properties.

Moreover, the possibility of curing the adhesive composition of thepresent invention by exposure to radiation of low energy (likeviolet-blue radiation having wavelength in the range of from 400 to 500nm) allows to avoid the alteration, or even the destruction, of thebiological substances like proteins, enzymes, antibodies and antigenscontained in the biomedical device. This is particularly advantageouswhen curing the adhesive composition for assembling components (likecovers) of biological devices already filled with biological fluids thatcould be altered, or even destroyed, by the exposure to radiation ofhigh energy (like UV radiation having wavelength lower than 400 nm).

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become more apparent from thedetailed description of a preferred, but not exclusive, embodiment of abiological device assembled with the adhesive composition of the presentinvention. This description will be set out hereinafter with referenceto the accompanying drawings, given by way of non-limiting example, inwhich

FIG. 1 is a schematic cross sectional view of an embodiment of theejection head of the biological device of the present invention; and

FIG. 2 is a schematic cross sectional view of an embodiment of thebiological device of the present invention.

FIG. 3 is a schematic cross sectional view of an embodiment of themicroarray biochip of the present invention.

FIG. 4 is a schematic top view of an embodiment of the microarraybiochip of the present invention.

DETAILED DESCRIPTION

The following will describe, with reference to the figures, a preferredembodiment of the invention.

FIG. 1 shows the ejection head 1 of a biomedical device according to thepresent invention. The ejection head comprises a substrate 2, a barrierlayer 4 and a nozzle layer or plate 7. The substrate 2 is generally madeof silicon. The substrate 2 has supply channels 5 and, on the surfacefacing the barrier layer 4, several metallic layers (not shown) to makeup the actuating element, typically a heating element or a piezoelectricelement, and the active electronic components. The barrier layer 4 ismade of photopolymer. The barrier layer comprises a set of ejectionchambers 6 and the microhydraulic channels (not shown) realized by meansof photolithographic techniques The nozzle layer or plate 7 comprisesorifices 3 in the correspondence of the actuating element.

The substrate 2 on the surface opposite the barrier layer 4, supports asecond barrier layer 8 made of photopolymer, wherein a set of channels 9are realized by means of photolithographic techniques. The channels 9are communicating with the supply channels 5 of the silicon substrate 2.Alternatively, as shown in FIG. 2, the second barrier layer 8 can beomitted and the channels 9 are directly realized by etching techniqueswithin the silicon substrate 2.

A layer 10 provided with supply channels 11 is joined onto the secondbarrier layer 9, or alternatively onto the silicon substrate 2. In thelatter case, the proper adhesion of the layer 10 to the siliconsubstrate 2 is obtained by means of the adhesive composition of thepresent invention. The layer 10 can be made of glass or plastic, likePMMA or SAN.

FIG. 2 shows the ejection head 1 of FIG. 1, further provided with twoadditional layers 12 and 13 having supply channels 14, reservoirchambers 15 and supply openings 16 for supplying the biological fluidfrom a pipette 17. The additional layers 12 and 13 can be made of glassor plastic, like PMMA or SAN. The proper adhesion of the lower and uppersurface of layer 12 to layers 10 and 13, respectively, is obtained bymeans of the adhesive composition of the present invention. Moreover,the adhesive composition of the present invention is sprayed in such away to form, after curing, a layer covering the whole surface of thechannels and chambers realized into the plastic or glass layers 10, 12,13, and the silicon substrate 2. As explained above, the cured adhesivecomposition layer provides to the walls of such channels and chambersthe proper biocompatibility and wettability without the need ofexpensive and potentially damaging treatments.

FIGS. 3 and 4 show different views of an embodiment of a microarraybiochip 20 according to the present invention. The microarray biochip 20comprises a transparent substrate 21 on which a suitable pattern ofseveral different biomolecules 22 has been deposited, and a chamber 23to confine biological samples (serum, blood, cells, oligomers and so on)and reagents. The chamber is realized within a photo-patterned polymericlayer 24. A cover 25 closes the microarray biochip 20. The cover 25 isprovided with input and output holes 26 to introduce and then wash awaythe biological samples and reagents. A thin layer of acrylic adhesivecomposition 27 is interposed between the photo-patterned polymeric layer24 and transparent substrate 21 to join them together. The acrylicadhesive composition is applied, for example, by spraying method, to theassembly of the cover 25 and polymeric layer 24 after the photo-etchingof the polymeric layer 24 to form the chamber 23. Accordingly, a thinlayer of acrylic adhesive composition 28 is also deposited on the coveras well as on the walls of both the chamber 23 and the input and outputholes 26. This allows to provide the proper wettability andbiocompatibility to the walls contacting the biological samples andreagents, avoiding both the retaining of biological compounds and/or therelease of contaminants.

The present invention will be further illustrated below by means of anumber of preparation and evaluation examples of adhesive composition,which are given for purely indicative purposes and without anylimitation of this invention.

EXAMPLES

A set of adhesive compositions according to the present invention hasbeen prepared by using the ingredients and the amount of the followingTable 1.

TABLE 1 TMPEOTA PETA PEGMM BYK310 IMPP EC 1 EC 2 A174 AB11 — 71 20.0 — 9— — — AB12 74.1 — 21.9 0.03 — 4 — — AB12.1 69.2 — 21.8 0.03 — 9 — — AB1571.1 — 21.8 0.03 — — 7 — AB31 70.1 — 17.8 0.03 — — 12 — AB34 70.0 — 14.00.03 — 4 12 — AB34.1 70.0 — 13.9 0.10 — 4 12 — AB35 68.9 — 10.0 0.10 — 412 5 AB36 66.5 — 8.4 0.10 — 4 12 9 AB37 75.7 — 11.0 0.10 — — 7.7 5.5AB38 73.0 — 9.3 0.10 — — 7.7 10 AB39 55.0 — 21.9 0.10 — 4 12 7 AB40 62.0— 23.2 0.10 — — 7.7 7 TMPEOTA: ethoxylated trimethylolpropanetriacrylate, available from Aldrich PETA: pentaerythritol triacrylate,available from Aldrich PEGMM: polyethylene glycol monomethacrylate,available from Aldrich BYK310: polyester modified dimethyl polysiloxane,available from Byk Chemie; Wallingford, Conn HMPP:Hydroxymethylpropiophenone, available from Aldrich EC 1: Esacure One 75,available from Lamberti EC 2: Esacure KTO-46, available from LambertiA174: γ-methacryloxypropyltrimethoxysilane, available from UnionCarbide.

Adhesion Test

The above described adhesive compositions were tested for evaluatingtheir adhesion strength on different materials.

Each adhesive composition was employed to adhere the sample materialsidentified in the following Table 2. The samples were prepared byspraying the surface to be joined with adhesive composition. Aftercontacting the surfaces to be joined, the adhesive composition was curedby exposure to UV-blue radiation. When using formulation containing onlythe EC2 photoinitiator, absorbing in the blue-violet region of thevisible spectrum the exposure was made by using a LED system emittingfrom 415 to 435 nm produced by CCS Europe NV, Belgium. When usingformulation containing the EC1 photoinitiator, absorbing in the UVregion, either alone or in combination with EC2, the exposure was madeby using a D lamp emitting from 200 to 450 nm produced by Fusion UVSystems GmbH. The radiated energy was about 800 mJ/cm².

The evaluation was made by measuring the breaking load or by detachingthe sample materials by knife and visually observing the kind ofdetachment.

Knife Test

This simple test requires the use of a utility knife to separate twosubstrates adhered with a cured layer of adhesive composition. The testis able to establish whether the adhesion is at a generally adequatelevel. Performance is based on both the degree of difficulty to detachthe substrates and the observation of the kind of detachment. The knifeis forced between the two adhered surfaces and then the knife is used toproduce a force perpendicular to the adhered surfaces, until to reach acomplete detachment or a rupture of the sample. The detached surfacesare then observed to the optical microscope to evaluate theirappearance.

Breaking Load Test

This test was performed by measuring with an Instron instrument the loadneeded to detach a first square sample of 5 cm² adhered to a secondsample of the same material. In correspondence of the centre of thefirst sample, the second sample had a hole through which the load forceis applied to the first sample until to provoke the detachment or therupture. The measure of the load force was made by using an Instroninstrument. The breaking load reported in Table 2 refers to the valueobtained for detaching the sample of 5 cm².

TABLE 2 PMMA/ SAN/ SILICON/ PMMA/PMMA GLASS GLASS GLASS Breaking load(Kg) Knife detachment AB11 11 A A B C AB12 23 B A B C AB12.1 17 A A B CAB15 20 A A B C AB31 13 A A B C AB34 20 B A B C AB34.1 20 B A B C AB3522 B B B C AB36 24 B B B C AB37 20 A B B C AB38 20 A B B C AB39 16 A A BC AB40 12 A A B C A Detachment of the adhesive B Delamination of theadhesive C Delamination of the adhesive and glass rupture

The observation of the detachment by visual inspection with the opticalmicroscope revealed three kinds of detachment. Detachment A is notdesired. The detachment of the adhesive from the substrate meant thatthe adhesive force was weak. On the contrary, detachment B, and evenmore, detachment C was desired. Detachments B and C meant that theadhesive force was strong, and in particular, that it was stronger thanthe cohesive forces of the same adhesive material

Storage Test in Air at Low Temperature

Another set of the same sample materials of Table 2 were stored for oneweek and three weeks at a temperature of about −10° C. After storage,samples were immersed in an aqueous solution of iophenoxic acid andrhodamine to check the presence of detachment areas. The results aresummarized in Table 3.

TABLE 3 PMMA/ PMMA/ SAN/ SILICON/ PMMA GLASS GLASS GLASS 1 W 3 W 1 W 3 W1 W 3 W 1 W 3 W AB11 NO NO YES YES NO YES NO NO AB12 NO NO YES YES NOYES NO NO AB12.1 NO NO YES YES NO YES NO NO AB15 NO NO YES YES NO YES NONO AB31 NO NO YES YES NO YES NO NO AB34 NO NO YES YES NO YES NO NOAB34.1 NO NO YES YES NO YES NO NO AB35 NO NO NO NO NO NO NO NO AB36 NONO NO NO NO NO NO NO AB37 NO NO NO NO NO NO NO NO AB38 NO NO NO NO NO NONO NO AB39 NO NO YES YES NO YES NO NO AB40 NO NO YES YES NO YES NO NO

Storage Test in Water at Room Temperature

A set of different material samples were sprayed with the abovedescribed adhesive compositions and cured under the same conditionsdescribed above. The samples were immersed in water at room temperatureand stored for one week and three weeks. After storage, the chemicalresistance and the adhesion of the cured adhesive composition layer wasevaluated by visual inspection with an optical microscope of detachmentareas. The results are summarized in Table 4.

TABLE 4 PMMA SAN GLASS SILICON 1 W 3 W 1 W 3 W 1 W 3 W 1 W 3 W AB11 NONO NO NO NO NO NO NO AB12 NO NO NO NO YES YES YES YES AB12.1 NO NO NO NOYES YES YES YES AB15 NO NO NO NO YES YES YES YES AB31 NO NO NO NO YESYES YES YES AB34 NO NO NO NO YES YES YES YES AB34.1 NO NO NO NO YES YESYES YES AB35 NO NO NO NO NO NO NO NO AB36 NO NO NO NO NO NO NO NO AB37NO NO NO NO NO YES NO YES AB38 NO NO NO NO NO YES NO YES AB39 NO NO NONO YES YES YES YES AB40 NO NO NO NO YES YES YES YES

The data shown above demonstrated that all tested adhesive compositionsexhibited a good adhesion between glass and silicon and between SAN andglass.

The adhesive compositions AB12, AB34, AB34.1, AB35 and AB36 showed thebest results of adhesion between two samples of PMMA.

The adhesive compositions AB34 and AB34.1 showed the best results ofadhesion between glass and SAN.

The adhesive compositions AB35 and AB36 showed the best results ofadhesion between glass and PMMA.

The adhesive compositions AB35 and AB36 showed good adhesion between alltested materials and also a good resistance under the storage conditionsboth at temperature below zero and under immersion in water. Theadhesive compositions AB37 and AB38 have comparable good adhesion andgood resistance under the storage conditions at temperature below zero,but the cured layer on glass and silicon showed detachment areas afterthree weeks of storage under water, probably due to the lower amount ofphotoinitiators.

Wettability/Viscosity Test

The following Table 5 summarizes the results of the measurement of thewettability and viscosity.

The wettability was evaluated by measuring the contact angle of a dropof water on a cured adhesive composition layer by using a OCA 40 MicroAutomatic Contact Angle measuring apparatus (produced by DataPhysicsInstruments GmbH, Germany).

The viscosity was measured by using a dynamic oscillatory mechanicalrheometer (Viscotech, Rheologica Instruments AB, Sweden).

TABLE 5 Contact angle Viscosity (°) (cP) AB11 50 170 AB12 30 79 AB12.130 81 AB15 30 50 AB31 30 53 AB34 30 82 AB34.1 30 81 AB35 37 58 AB36 3855 AB37 35 48 AB38 38 42 AB39 31 57 AB40 30 45

The invention claimed is:
 1. A biomedical device for the distribution orcontainment of biological substances, wherein the biomedical devicecomprises at least two components adhered together with an adhesivecomposition comprising at least one polyol tri(meth)acrylate monomer andat least one polyalkylene glycol mono(meth)acrylate monomer.
 2. Thebiomedical device according to claim 1, wherein said polyoltri(meth)acrylate monomer is selected from the group consisting ofditrimethylolpropane triacrylate (DiTMPTTA),iris-(2-hydroxyethyl)-isocyanurate triacrylate (THEICTA),dipentaerythritol triacrylate (DiPETA), ethoxylated trimethylolpropanetriacrylate (TMPEOTA), propoxylated trimethylolpropane triacrylate(TMPPOTA), ethoxylated pentaerythritol triacrylate (PETEOIA),propoxylated glyceryl triacrylate (GPTA), pentaerythritol triacrylate(PETA), trimethylolpropane triacrylate (TMPTA) and modifiedpentaerythritol triacrylate, triethyleneglycol trimethacrylate(TTEGTMA), tetraethyleneglycol trimethacrylate (TTEGTMA),polyethyleneglycol trimethacrylate (PEGTMA), trihydroxyhexanetrimethacrylate (HTTMA), ethoxylated bisphenol A trimethacrylate, andtrimethylolpropane trimethacrylate (TMPTMA).
 3. The biomedical deviceaccording to claim 1, wherein said adhesive composition comprises fromabout 40% to about 90% by weight, based upon the total weight of saidadhesive composition, of said at least one polyol tri(meth)acrylatemonomer.
 4. The biomedical device according to claim 1, wherein saidpolyalkylene glycol mono(meth)acrylate monomer is selected from thegroup consisting of polypropylene glycol monomethacrylate, polyethyleneglycol monomethacrylate, polyethylene glycol-polypropylene glycolmonomethacrylate, polypropylene glycol monoacrylate, polyethylene glycolmonoacrylate, polypropylene glycol-polytrimethylene monoacrylate,polyethylene glycolpolytetramethylene glycol monomethacrylate,methoxypolyethylene glycol monomethacrylate,perfluorealkylethyl-polyoxyalkylene mono methacrylate, and combinationsthereof.
 5. The biomedical device according to claim 1, wherein saidadhesive composition comprises from about 5% to about 35% by weight,based upon the total weight of said adhesive composition, of said atleast one polyalkylene glycol mono(meth)acrylate monomer.
 6. Thebiomedical device according to claim 1, wherein said adhesivecomposition comprises from about 1% to about 25% by weight based uponthe total weight of the composition of at least one radical initiatorselected from the group of initiators sensitive to UV and/or blueradiation (photoinitiator) and thermal initiators (thermoinitiator). 7.The biomedical device according to claim 6, wherein said photoinitiatoris selected from the group consisting of2,2′-(2,5-thiophenediyl)bis(5-tert-butybenzoxazole); 1-hydroxycyclohexylphenyl ketone; 2,2-dimethoxy-2-phenylacetophenone; xanthone; fluorenone;anthraquinone; 3-methylacetophenone; 4-chlorobenzophenone;4,4′-dimethoxybeniophenone; 4,4′-diaminobenzophenone; Michler's ketone;benzophenone; benzoin propyl ether; benzoin ethyl ether; benzyl dimethylketal, 1-(4-isopropylphenyl)-2hydroxy-2-methylpropane-1-one;2-hydroxy-2-methyl-1phenylpropane-1one; methylbenzoyl formatethioxanthone; diethylthioxanthone; 2-isopropylthioxanthone;2-chlorothioxanthone;2-methyl-1-(4-(methylthio)phenyl)-2-morpholinopropane-1-one; and2,4,6-trimethylbenzoyidiphenylphosphine oxide.
 8. The biomedical deviceaccording to claim 6, wherein said thermoinitiator is selected from thegroup consisting of organic peroxides and azo compounds.
 9. Thebiomedical device according to claim 1, wherein said adhesivecomposition comprises from about 0.01% to about 2% by weight of asiloxane flow agent, based upon the total weight of the composition. 10.The biomedical device according to claim 1, wherein said adhesivecomposition comprises from about 1% to about 20%, based upon the totalweight of the composition, of at least one silane coupling agent. 11.The biomedical device according to claim 1, wherein said adhesivecomposition comprises from about 1% to about 20%, based upon the totalweight of the composition, of at least one oxygen scavenger.
 12. Thebiomedical device according to claim 11, wherein said oxygen scavengeris selected from the group consisting of substituted phenols andaromatic amines.
 13. A biomedical device for the distribution orcontainment of biological substances comprising at least one surfacethereof covered with a cured acrylic adhesive composition layer having awettability equal to or lower than 50°.
 14. The biomedical deviceaccording to claim 13 wherein said cured acrylic adhesive compositionlayer is made with an adhesive composition comprising at least onepolyol tri(meth)acrylate monomer and at least one polyalkylene glycolmono(meth)acrylate monomer, and the biomedical device comprises at leasttwo components adhered together with the adhesive composition.
 15. Thebiomedical device according to claim 13, wherein said biomedical devicecomprises a thermal or piezoelectric ejection head comprising anorifice, an ejection chamber and an actuating element on a siliconsubstrate, at least one barrier layer, and at least one additionallayer, which may be a cover layer.
 16. The biomedical device accordingto claim 15, wherein said biomedical device further comprises reservoirchambers and supply openings.
 17. The biomedical device according toclaim 13, wherein said biomedical device comprises a transparentsubstrate a chamber realized within a photo-patterned polymeric layer tocontain biological samples and reagents, and a cover provided with inputand output holes to introduce and then wash away said biological samplesand reagents.